The development of therapeutic products to restore or replace the function of impaired connective tissues has been stimulated by an aging population, bone donor scarcity and the potential of transmission of infectious diseases. Due to the self-regenerative capacity of bone and cartilage, there has been extensive research into the development of biomaterials which support tissue induction from of repairative tissue surrounding tissue.
One approach to tissue repair involves the administration of growth factors in solution with an appropriate delivery system at the desired tissue site. See Kenley et al., Pharm. Res. 10:1393 (1993); Anderson et al., Curr. Opin. Ther. Patents, 4:17 (1994). A primary inducer of mesoderm formation in embryogenesis, bFGF, apparently plays a role in osteogenesis. Bone morphogenic proteins (BMPs), members of the transforming growth factor superfamily of proteins, are bone inducers. Sampath et al., J. Biol. Chem., 267:20352 (1992); Wozney et al., Science, 242:1528 (1988). These molecules are involved in cell proliferation and differentiation both in vitro and in vivo. The biological functions of these growth factors are mediated by the interaction of the growth factors with high-affinity cell-surface receptors and subsequent alterations in gene expression within the stimulated cells.
However, development of effective delivery systems for these growth factors has been a major obstacle. The development of an effective and reliable delivery system is crucial to the viable use of growth factors in bone or cartilage repair. Synthetic polymeric prostheses, inorganic ceramics, hydrogels, and injectable vehicles from natural or synthetic polymers have been investigated with the intention of localizing and sustaining active agents at the administered site, but it has been difficult to create a delivery system that incorporates growth factor stability and optimal release profiles. See Hollinger et al., J. Craniofac. Surg. 4:115 (1993); J. Control. Red. 39:287 (1996); Miyamoto et al., Clin. Orthop. Red. Res., 274:266 (1992).
Hyaluronic acid is a natural component of the extracellular matrix of most tissues and is readily sterilized, is biodegradable and can be produced in a wide range of consistencies and formats. It is generally water-soluble, biocompatible and its resorption characteristics can be controlled by the manipulation of monomers. It is a linear polymer made up of repeating glycosaminoglycan (GAG) disaccharide units of D-glucuronic acid and N-acetylglycosamine in .beta.(1-3)and .beta.(1-4) linkages.
Sulfated GAGs, such as dermatan sulfate, heparan sulfate, chondroitin sulfate and keratan sulfate are found mostly in the extracellular matrix and on the cell surface as proteoglycans. These macromolecules are secreted by cells and play a role in both signal transduction and storage of some growth factors such as FGFs, TGF-.beta.s and BMPs. See Viodavsky et al., PNAS, 84:2292 (1987); Nakagawa et al., Exp. Cell Res. 182:572 (1989). Hyaluronic acid and sulfated GAGs are easily sterilized, biodegradable, and can be produced in a wide range of consistencies and formats. See Robinson et al., Calcif. Tissue Int., 46:246 (1990).